DE3208628A1 - NEW COMPOUNDS, METHOD FOR THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS - Google Patents

Abstract

Compounds of the formula <IMAGE> in which R is an optionally substituted aryl or heterocyclic radical, R1 is a hydrocarbon radical which is optionally interrupted by 1 oxygen atom in the chain, and/or which is optionally substituted, R4 is an aliphatic hydrocarbon radical having 7 to 14 carbon atoms, which is optionally interrupted by one oxygen atom and/or which is optionally substituted, R2 and R3 each independently is hydrogen, an alkyl radical, an aryl radical or an aralkyl radical, or, for the case where one of the substituents R2 or R3 has the above-mentioned meaning, the other is hydroxymethyl, acetoxymethyl or amino, and X is N-R5, wherein R5 is hydrogen, an alkyl radical which is optionally interrupted by an oxygen atom, a morpholinoalkyl radical, an aryl radical or an aralkyl radical or X is an oxygen atom, when one of the radicals R2 or R3 denotes an amino group, or pharmaceutically acceptable acid addition salts thereof, exhibit hypotensive activity.

Description

Patents, trademarks and licenses KS / bc / c

^Γ March 9, 1982

Pha Ib

New compounds, processes for their preparation and their use as pharmaceuticals

The present invention relates to novel compounds having prolonged circulatory activity, several methods for their production and their use as drugs that influence the circulation, in particular as antihypertensive agents.

It has already become known that diethyl 1,4-dihydro-2,6-dimethyl-4-phenyl-pyridine-3,5-dicarboxylate can be used obtained when ethyl 2-benzylidene acetoacetate is obtained with ß-aminocrotonic acid ethyl ester or acetoacetic acid ethyl ester and ammonia (E. Knoevenagel, Ber. dtsch. former Ges. 3J_, 743 (1898)).

It is also known that certain 1,4-dihydropyridines have interesting pharmacological properties (F. Bossert, W. Vater, Naturwissenschaften 58, 578 (1971)).

Furthermore is from the German disclosure regulations 2 117 571 and 2 117 573 have become known that similar

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Compounds can be used as coronary drugs and as antihypertensive agents.

With knowledge of this prior art, however, it could not be expected that the new invention Compounds have such a surprisingly long-lasting antihypertensive effect.

The invention relates to new compounds of the general formula (I)

R ¹ O ₂ CN _n A ^ Co ₂ R ⁴

in which

R for aryl or for thienyl, furyl, pyryl, pyrazolyl, Imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, Indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadxazolyl, quinolyl, isoquinolyl, Quinazolyl or quinoxalyl, the aryl radical and the heterocycles being given at least 1 to 2 identical or different substituents from the group phenyl, alkyl, alkoxy, Alkylene, dioxymethylene, halogen, trifluoromethyl, Polyfluoroalkoxy, nitro, cyano, azido or SO alkyl (m = 0 to 2) contain,

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-Z3 -

R for a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon residue, which is optionally through 1 oxygen atom in the chain is interrupted and / or which is optionally substituted by halogen, cyano, hydroxy, acyloxy, phenyl, phenoxy, or an amino group, in turn substituted by 2 identical or different substituents from the group consisting of alkyl, aryl or aralkyl is,

R stands for a straight-chain, branched or cyclic, saturated or unsaturated aliphatic Hydrocarbon radical with 7 to 14 carbon atoms, optionally by a Oxygen atom is interrupted, and / or optionally by halogen, hydroxy or acyloxy is substituted,

3

R and R are identical or different and each represent hydrogen, a straight-chain or branched one Alkyl radical, an aryl radical or an aralkyl radical,

or in the event that one of the substituents

2 3
R or R has the abovementioned meaning, the other being hydroxymethyl, acetoxymethyl or amino

and

X stands for N-R, where R for hydrogen, a straight-chain or branched one, optionally alkyl radical interrupted by an oxygen atom, a morpholinoalkyl radical, an aryl radical or an aralkyl radical or

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X stands for an oxygen atom if at least one:

tet,

2 3
one of the radicals R or R is an amino group

and their pharmaceutically acceptable acid addition salts.

The preparation of the compounds according to the invention can take place according to several methods, which are based essentially on the known Hantz pyridine synthesis. Depending on the nature of the different meanings of the substituents, the sub-variants below are this Synthesis described. Variants A) to G) each relate to the production of dihydropyridines. Variant H relates to a subsequent exchange of substituents in the 2-position of the dihydropyridine ring and variant J relates to the preparation of 4H-pyrans.

In the event that X in the general formula (I) stands for .N-R, where R has the meaning given above and

2 '3'
R and R each represent hydrogen, a straight-chain or branched alkyl radical, an aryl radical, an aralkyl radical or the acetoxymethyl group, the compounds according to the invention are preferably prepared by

Yliden-ß-ketoester of general. Formula (II)

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-ν / 5 -

/ CO R R-CH = C '(II)

in which

12 'R, R and R have the meaning given above, with enaminocarboxylic acid esters of the general formula (III)

R ³ '-C = CH-CO-R ⁴ (III)

5 '

R NH

in which

3 '5 R, R and R have the meaning given above,

optionally reacted in the presence of inert organic solvents, ρ or
B)
Ylidene-ß-ketoester of the general formula (II)

CO ₉ R ¹

R-CH = C ^ ₇ , (II) ^ COR

in which

1 2 "

R, R and R have the meaning given above,

with amines of the general formula (IV) and ß-ketocarboxylic acid esters of the general formula (V)

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R ⁵ -NH ₂ R ³ '.-CO-CH ₂ -CO ₂ R ⁴

(IV) (V)

in which

5.314 R, R and R have the meaning given above,

optionally reacts in the presence of inert organic solvents,

or

Ylidene-ß-ketoester of the general formula (VI)

01 (VI)

COR

' in which

3 'R, R and R have the meaning given above,

'' with enaminocarboxylic acid esters of the general formula (VII)

R ² '-C = CH-CO ₉ R ¹ (VII)

5 'R NH

in which

2 '5

. .R, R and R have the meaning given above,

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optionally reacts in the presence of inert organic solvents, or
D)
Ylidene-ß-ketoester of the general formula (VI)

R-CH = CC " \ y (VI)

COR

in which

3 'R ₁ . R and R have the meaning given above, with amines of the general formula (IV)

R ⁵ -NH ₂ (IV)

in which

R has the meaning given above,

and ß-ketocarboxylic acid esters of the general formula (VIII)

R ² '-CO-CH ₂ -CO ₂ R ¹ (VIII)

in which

2 '1 R and R have the meaning given above,

optionally in the presence of inert organic solvents implements

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or

E)

Aldehydes of the general formula (IX).

R-C. (IX)

in which

R has the meaning given above,

with enaminocarboxylic acid esters of the general formula (III)

R ³ '-C = CH-CO ₀ R ⁴ (III)

5 '
R NH

in which

3 '4 5
R, R and R have the meaning given above,

and with ß-ketocarboxylic acid esters of the general formula (VIII)

R ² -CO-CH ₂ -CO ₂ R ¹ (VIII)

in which

12 '
R and R which have the meaning given above,

optionally reacts in the presence of inert organic solvents,

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or

F)

Aldehydes of the general formula (IX)

R-C ^ (IX)

in which

R has the meaning given above,

with enaminocarboxylic acid esters of the general formula (VII)

R ² '-C = CH-CO ₀ R ¹ (VII)

51 ^ R NH

in which

1 2 'R, R and R have the meaning given above

and with ß-ketocarboxylic acid esters of the general formula (V)

'R ³ ' -CO-CH ₂ -CO ₂ R ⁴ (V)

in which

3 * 4

R and R have the meaning given above,

optionally reacts in the presence of inert organic solvents,

or

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G)

in the event that X in formula (I) denotes NH and

"3"
R or R represent an amino group, the compounds according to the invention are preferably prepared by

1. Ylidene-ß-ketoester of the general formula (II)

^ * COR

in which

1 2 R, R and R have the meaning given above,

2
but R not for an amino or hydroxymethyl

group stands,

with amidinoacetic acid esters of the general formula (X)

^H 2 ^N \ 4

^ C = CH-CO ₂ R (X)

in which

4th
R has the meaning given above,

optionally reacted in the presence of inert organic solvents or
2. Ylidene-ß-ketoester of the general formula (VI)

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.CO "R R-CH = CC ^, (VI)

in which

3 4
R, R and R have the meaning given above, but R does not represent an amino or hydroxymethyl group,

with aminoacetic acid esters of the general formula (XI)

HN

/ C = CH-CO ₉ R (XI)

^H 2 ^N

in which
R has the meaning given above,

optionally reacts in the presence of inert organic solvents,

or
H)

in the event that X in the general formula (I) stands for N-R, where R is as defined above has, and

Il I 3 "'

R or R stand for the hydroxymethyl group, the compounds according to the invention are preferably prepared by the corresponding invention

2 3 according to compounds in which R or R acetoxy

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Si

-vz-

methyl mean the conditions of an acidic or basic Subjected to hydrolysis, leaving the acetoxymethyl group is converted into a hydroxymethyl group,

or
I)

in the case that X is in the general formula (I)

2 "3"

Represents oxygen atom and R or R represents an amino group is, the compounds according to the invention are preferably prepared by

1. Ylidene-ß-ketoester of the general formula (II)

R-CH = C ^ · "(II)

^ - COR

in which

1 2
R, R and R have the meaning given above, but R does not represent the amino or hydroxymethyl group,

with Cyanessxgsaureestern of the general formula (XII)

N = C-CH ₂ -CO ₂ R ⁴ (XII)

in which

R has the meaning given above,

possibly in the presence of organic solutions

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Ji

- vs -

implements funds,
or

2. Ylidene-ß-ketoester of the general formula (VI)

^ -CO-R ⁴
R-CH = C o

in which

4 3
R, R and R have the meaning given above, but R does not represent the amino or hydroxymethyl group,

with cyanoacetic acid esters of the general formula (XIII)

N = C-CH ₂ -CO ₂ R ¹ (XIII)

in which

R has the meaning given above,

optionally in the presence of organic solvents to react.

The compounds according to the invention have valuable pharmacological properties. Especially due to their unexpected long-lasting circulatory impairment. They can have flowing effects as antihypertensive Agents, as vasodilators, as cerebral therapeutics and as coronary therapeutics are used and are therefore to be regarded as an enrichment of pharmacy.

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-H-

The long-lasting effect of blood pressure is of particular interest.

Depending on the type of starting materials used, the synthesis variants for the compounds according to the invention can be used can be represented by the following formula schemes:

H ₃ CO ₂ C

H ₃ CO ₂

H ₃ CO ₂

^CO 2 ^C 11 ^H 23

^H 5 ^C. 2 ^OC

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JS

- .TS -

* <f ^H 2 H

NO,

NO.

^ C -, -. Η «- Hr-C« O «
10 21 5 2 2

NH ₃ O ^ ^ CH ₃ ^2Η 2 ^Ο

2 10 2T

CH.

^H 3 ^CO 2 ^C \

NO,

NO,

• H ^H 3 ^C
Ί 1 23

H ^ X0 ₂ C_H _o "3 ^C0 2 ^C \ ^^ _VsX ^C0 2 ^C H ^H 23

+. 1 . -2H ₂ O

η ₂ ν ^ Ν: η ₃ ^η 3 _ _η

NO,

NH ₂

-2H ₂ O

H ₅ C ₂ O ₂ C

NO,

^ XO ₀ C _1n H

2 10

H ^ C ^^ N ^^ CH ^ H

NO,

^CO 2 ^C 10 ^H 21

NO.

^CO 2 ^C 10 ^H 21

N NH H

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H ₃ CO ₂ C

NO, O,

ΛH ₉ -OCOCH.

■ H "

H ₃ CO ₂ C

H-.CN CH ₉ OH H ^

C III N

NO,

/ ^CO 2 ^C 11 ^H 23

NNCH H

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J?

Of particular interest are those. compounds according to the invention of the general formula (I)

in which

R for phenyl, naphthyl or for thienyl, furyl, pyryl, Pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, Indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, quinolyl, isoquinolyl, Quinazolyl or quinoxal, the ring systems mentioned each having 1 or 2 identical or various substituents from the group consisting of phenyl, straight-chain or branched alkyl 1 to 8 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, alkoxy with 1 to 4 carbon atoms, Tri-, tetra- and pentamethylene, dioxymethylene, halogen, trifluoromethyl, trifluoromethoxy, Difluoromethoxy, tetrafluoroethoxy, nitro, Cyano, azido or SO-alkyl, in which m is a number from 0 to 2 and alkyl is preferably 1 to Contains 4 carbon atoms, may be substituted,

R for a straight-chain, branched or cycli- ■ see saturated or unsaturated hydrocarbon residue with up to 20 carbon atoms, which is optionally replaced by 1 oxygen atom is interrupted in the chain and / or the

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is optionally substituted by halogen, cyano, Hydroxy, acetoxy, phenyl, phenoxy or an amino group, which in turn is represented by 2 identical or different Substituents from the group consisting of alkyl having 1 to 4 carbon atoms, phenyl or benzyl is substituted,

R stands for a straight-chain, branched or cyclic, saturated or unsaturated aliphatic Hydrocarbon radical with 7 to 14 carbon atoms stands, which may be interrupted by an oxygen atom in the chain and / or which is optionally substituted by halogen, hydroxy or acetoxy,

3
R and R are identical or different and each represent hydrogen, a straight-chain or branched alkyl radical with up to 4 carbon atoms, a phenyl radical or a benzyl radical,

2 3 or one of the substituents R or R for a

Hydroxymethyl, acetoxymethyl or amino group, where the other substituent has the meaning given above,
and
X stands for NR, where R stands for hydrogen, a straight-chain or branched alkyl radical with up to 4 carbon atoms, optionally interrupted by an oxygen atom, a morpholinoacetyl radical, a phenyl radical or a benzyl radical,
or

0 stands for an oxygen atom, in which case one of the

2 3
Substituents R or R always mean an amino group.

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- 1 * 9 -

Compounds of the general formula (I) may be mentioned as preferred

in which

R represents phenyl, pyridyl, thienyl or furyl, where the phenyl ring optionally by one or two identical or different substituents from the Group phenyl, alkyl with 1 to 4 carbon atoms ,. Alkoxy with 1 to 2 carbon atoms, fluorine, chlorine, Bromine, trifluoromethyl, trifluoromethoxy, difluoromethoxy, Nitro, cyano, azido or alkyl! Mercapto substituted with 1 to 4 carbon atoms in the alkyl radical is,

R stands for a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical with up to 14 carbon atoms, which is optionally interrupted by an oxygen atom and / or which is optionally substituted by fluorine, chlorine, cyano, hydroxy or amino,

4th
R stands for a straight-chain, branched or cyclic, saturated or unsaturated aliphatic hydrocarbon radical with 7 to 12 carbon atoms which is optionally interrupted by an oxygen atom in the chain and / or which is optionally substituted by fluorine, chlorine, hydroxy or acetoxy,

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- 20 -

3 R and R are identical or different and each represent hydrogen, alkyl with 1 to 2 carbon atoms, Phenyl or benzyl

or

2 one of the substituents R or R for a hydroxymethyl, Acetoxymethyl or amino group, where the other substituent has the meaning given above,

X stands for N-R, where R stands for hydrogen, an alkyl radical with up to 4 carbon atoms or optionally is interrupted by an oxygen atom, a morpholinoalkyl radical with 1 to 4 carbon atoms in the alkyl part, a phenyl radical or a benzyl radical,

or

stands for an oxygen atom where one of the substitutes] means.

2

Substituents R or R always an amino group

Particular emphasis should be given to compounds of the general formula (I)

in which

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R represents a phenyl radical which has one or two identical or different substituents from the Group chlorine, trifluoromethyl, nitro or cyano contains

or represents a benzoxadiazolyl radical,

R represents a straight-chain or branched hydrocarbon radical with up to 7 carbon atoms, which is optionally interrupted by an oxygen atom in the chain and / or which optionally is substituted by fluorine or chlorine or an amino group, which in turn is substituted by two methyl groups or can be substituted by a methyl and a benzyl group,

4th
R denotes a straight-chain, branched or cyclic, saturated or unsaturated aliphatic hydrocarbon radical with seven to twelve carbon atoms, which is optionally interrupted by an oxygen atom in the chain or which is optionally substituted by fluorine, chlorine or hydroxyl,

3
R and R each represent hydrogen or an alkyl radical with 1 to 2 carbon atoms,

2 3 or one of the substituents R or R represents the amino group, the other substituent has the meaning given above, and

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X stands for N-R / where R is a hydrogen atom or represents an alkyl radical with up to 3 carbon atoms,

or

stands for an oxygen atom, where one of the substituents

represents.

2 3
Substituents R or R always an amino group

Process variant A

According to method A, a ylidene-ß-ketoester of the general Formula II

CO ₂ R ¹

R-CH = C "(II)

with an enamoxnocarboxylic acid ester of the general formula III

R ³ -C = CH-C0 ₉ R ⁴ (III)

5 '
R NH

brought to reaction.

The ylidene-ß-ketoesters used as starting materials

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of the general formula (II) are known from the literature or can be prepared by methods known from the literature (cf. e.g. G. Jones "The Knoevenagel Condensation" in Org. Reactions, Vol. XV, 204 ff (1969)).

Examples are:

Benzylidenformylessigsäuremethylester, Benzylidenacetessigsäuremethylester, 2'-Nitrobenzylidenacetessigsäureethylester, 3'-Nitrobenzylidenacetessigsäure n-butyl, 3'-Nitrobenzylidenacetessigsäuredecylester, 3'-Nitrobenzylidenacetessigsäuredodecylester, 3'-Nitrobenzylidenacetessigsäuretetradecylester, 2 ^1, 3 'Dichlorbenzylidenacetessigsäureethylester, 2', 3'-Dichlorbenzylidenacetessigsäuredecylester, 2 '-Chlorobenzylideneacetoacetic acid hexadecyl ester, 3'-chlorobenzylideneacetoacetic acid (2-propoxyethyl) ester, 3-cyanobenzylideneacetoacetic acid (2-chloroethyl) ester, 2'-chlorobenzylideneacetoacetic acid (2.2.2-trifluoroethyl) ester,

2'-trifluoromethylbenzylideneacetoacetic acid (2-cyanoethyl) ester,

2'-Difluoromethoxybenzylideneacetoacetic acid (2-acetoxyethyl) ester,
3-methylsulfonylbenzylideneacetoacetic acid (2-phenoxyethyl) ester,

3'-nitrobenzylideneacetoacetic acid (2-N-benzyl-N-methy1-aminqethyl) ester,

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3'-Nitrobenzylidenpropionylessigsäureisopropylester, 2 '-Nitrobenzylidenacetessigsöurecyclopentylester, 2'-Nitrobenzylidenacetessigsäureisobutylester, 3'-Nitrobenzylidenacetessigsäureneopentylester, 3'-Nitrobenzylidenacetessigsäureallylester, cC-acetyl-.beta. (pyridyl-3) -acrylic acid ethyl ester, ot * -acetyl-.beta. (pyridyl-3 ) Octyl acrylate, ⁰ ^ -acetyl-β- (pyridyl-3) -acrylic acid decylester, ^ -acetyl-β- (pyridyl-3) -acrylic acid tetradecyl ester, ^ -acetyl-β- (benzoxadiazolyl-4) -acrylic acid ethyl ester.

The enaminocarboxylic acid esters used as starting materials of the general formula (III) are known from the literature or can be prepared by methods known from the literature (cf. A. C. Cope, J. Amer. former Soc. £ 7,1017 (1945)).

Examples are:

ß-aminocrotonic acid heptyl ester, ß-aminocrotonic acid octyl ester,.

ß-aminocrotonic acid onyl ester, ß-aminocrotonic acid decyl ester, ß-aminocrotonic acid undecyl ester, ß-aminocrotonic acid dodecyl ester, ß-aminocrotonic acid tetradecyl ester, ß-aminocrotonic acid (2-pentyloxyethyl) ester, ß-aminocrotonic acid (2-hexyloxyethyl) ester, ß-aminocrotonic acid heptyl ester, ß-aminocrotonic acid octenyl ester,

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-VS-

ß-aminocrotonic acid (u? -chlorheptyl) ester, ß-aminocrotonic acid (LD -chlorodecyl) ester, ß-aminocrotonic acid (Ll? -hydroxydecyl) ester, ß-aminocrotonic acid ( u) -acetoxydecyl) ester, ß-aminocrotonic acid (Lj -hydroxyundecyl) tester, ß-aminocrotonic acid (u) -acetoxyundecyl) ester, ß-methylaminocrotonic acid decyl ester, ß-benzylaminocrotonic acid decyl ester, ß-amino-ß-ethyl-acrylic acid decyl ester, ß-amino acid decyl ester, ß-amino acid acrylic acid decyl ester, ß-amino-ß-benzyl-acrylic acid decyl ester, ß-amino-ß-acetoxymethyl-acrylic acid decyl ester, ß-amino-ß-acetoxymethyl acrylic acid undecyl ester.

All inert organic solvents are suitable as diluents. These preferably include alcohols such as ethanol, methanol, isopropanol, ethers such as dioxane, diethyl ether, tetrahydrofuran, glycol monomethyl ether, Glycol dimethyl ether or glacial acetic acid, dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine and Hexamethylphosphoric triamide.

The reaction temperatures can be varied over a wide range. In general, between 20 and 150 ^° C., preferably between 20 and 100 ^° C., in particular at the boiling point of the respective solvent.

The reaction can take place at normal pressure, but also at

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- 26 -

carried out at high pressure. Generally works one under normal pressure.

When carrying out the method according to the invention one mole of the ylidene-ß-keto ester of the formula (II) with one mole of enaminocarboxylic acid ester of the formula (III) reacted in a suitable solvent. The isolation and purification of the invention Substances are preferably carried out in such a way that the solvent is distilled off in vacuo and the if appropriate, residue obtained in crystalline form from a 'suitable solvent only after cooling with ice recrystallized.

Process variant B

According to method B, a ylidene-ß-ketoester of the general Formula II

R-CH = C * (II)

^ COR ²

with an amine of the general formula (IV) and a ß-ketocarboxylic acid ester of the general

R ⁵ -NH ₂ R ³ -CO-CH ₂ -CO ₂ R ⁴

(IV) (V)

Formula (V) brought to reaction.

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Examples of the Ylidenß-ketoesters used as starting substances of the general formula II are already listed under process variant A.

The amines of the formula (IV) which can be used according to the invention are already known.

Examples are:

Ammonia, methylamine, n-propylamine, isopropylamine, butylamine, ß-methoxyethylamine, benzylamine, 2- (N-mprpholinyl) -ethylamine.

The ß-ketocarboxylic acid esters used as starting materials of the general formula (V) are known from the literature or can be prepared by methods known from the literature (e.g. D. Borrmann, "Conversion of diketene with alcohols, phenols and mercaptans", in Houben-Weyl, Methods of Organic Chemistry, Vol. VII / 4, 230 ff (1968); Y. Oikawa, K. Sugano, and O. Yonemitsu, J. Org. Chem. 43, 2087 (1978)).

Examples are:

Heptyl acetoacetate,
Onyl acetoacetate,
Acetoacetic acid decyl ester,
Undecyl acetoacetate,
Tetradecyl acetoacetate,
Acetoacetic acid (2-pentyloxyethyl) ester,

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Heptenyl acetoacetate,
Acetoacetic acid (CJ -chlorheptyl) ester, acetoacetic acid (LC -hydroxydecyl) ester, acetoacetic acid ^ lC-acetoxyundecyl) ester, ■ 5 propionyl acetic acid decyl ester,
Butyrylacetic acid decyl ester.

All inert organic solvents are suitable as diluents. These preferably include Alcohols such as ethanol, methanol, isopropanol, ethers such as dioxane, diethyl ether, tetrahydrofuran, glycol monomethyl ether, Glycol dimethyl ether or glacial acetic acid, dimethylformamide, Dimethyl sulfoxide, acetonitrile, pyridine and hexamethyl phosphoric acid triamide.

The reaction temperatures can be varied over a wide range. In general, one works between 20 and 150 ⁰ C, but preferably at the boiling point of the respective solvent.

The reaction can be carried out under normal pressure, but also under increased pressure. Generally works one under normal pressure.

When carrying out the method according to the invention the substances of the formulas (II), (IV) and (V) involved in the reaction are used in each case in molar amounts. The amine used is expediently added in an excess of 1 to 2 mol. The inventive

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According to compounds can easily by recrystallization be cleaned from a suitable solvent,

Process variant C

According to method C, a ylidene-ß-ketoester of the general Formula (VI)

CO ₂ R ¹

R-CH = C (VI)

COR ³

with an enaminocarboxylic acid ester of the general formula (VII)

RC-CH-CO ₉ R (VII)

51 ^

RNH

0 brought to reaction.

The ylidene-ß-ketoesters used as starting materials of the formula (VI) are known from the literature or can be prepared by methods known from the literature (cf. e.g. G. Jones "The Knoevenagel Condensation" in Org. Reactions, Vol. XV, 204 ff (1967)).

Examples are:

Heptyl benzylidene acetoacetate, heptyl 3'-nitrobenzylidene acetoacetate,

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2 '-chlorobenzylidene acetyl acetate, 2'-Cyanobenzylidenacetoacetic acid onyl ester, 3'-Nitrobenzylidenacetoacetic acid decyl ester, 2'-trifluoromethylbenzylideneacetoacetic acid decyl ester, 2 ', 3'-dichlorobenzylideneacetoacetic acid decyl ester, 3'-nitrobenzylideneacetoacetic acid undecyl ester, 3'-nitrobenzylidene acetoacetic acid dodecyl ester,

3 '-nitrobenzylidene acetoacetic acid tetradecyl ester,

2'-nitrobenzylideneacetoacetate (2-pentoxyethyl) ester, 3'-nitrobenzylideneacetoacetic acid ( LO -chlorodecyl) ester, 3'-nitrobenzylideneacetoacetic acid ( uO -hydroxydecyl) ester, 3'-nitrobenzylideneacetoacetic acid (uO -hydroxydecyl ) -acetoxyacetate -ester, 'X -acetyl-ß- (pyridyl-3) -acrylic acid decyl ester, ' ^y - -acetyl-ß- (pyridyl-2) -acrylic acid decyl ester, ° <- -propionyl-ß- (pyridyl-3) -acrylic acid decyl ester,

• OC -acetyl-ß- (benzoxadiazolyl-4) -acrylic acid decyl ester, & ■ -acetyl-ß- (2-methylthio-pyridyl-3) -acrylic acid decyl ester.

The enaminocarboxylic acid esters of the formula (VII) used as starting materials are known from the literature or can be prepared by methods known from the literature (cf. AC Cope, J. Amer. Chem. Soc. §Ί_, 1017 (1945)).

Examples are:

ß-aminocrotonic acid hexyl ester, ß-aminocrotonic acid octyl ester, ß-aminocrotonic acid decyl ester, ß-aminocrotonic acid tetradecyl ester, ß-aminocrothonic acid isopropyl ester,

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ß-aminocrotonic acid cyclopentyl ester, ß-aminocrotonic acid benzyl ester, ß-aminocrotonic acid allyl ester / ß-aminocrotonic acid (2-methoxyethyl) ester, ß-aminocrotonic acid (2-propoxyethyl) ester, ß-aminocrotonic acid (2.2.2-trifluoroethyl) ester, ß-aminocrotonic acid (2-chloroethyl) ester, ß-aminocrotonic acid (2-cyanoethyl) ester, ß-aminocrotonic acid (2-hydroxyethyl) ester, ß-aminocrotonic acid (2-acetoxyethyl) ester, ß-aminocrotonic acid (2-phenylethyl) ester, ß-aminocrotonic acid (2-phenoxyethyl) ester, ß-aminocrotonic acid (2-dimethylaminoethyl) ester, ß-aminocrotonic acid (2-N-benzyl-N-methyl-aminoethyl) ester, ß-methylaminocrotonic acid ethyl ester, ß-Butylaminocrotonic acid ethyl ester, ß-Benzylaminocrotonic acid ethyl ester.

All inert organic solvents are suitable as diluents. These preferably include Alcohols such as ethanol, methanol, isopropanol, ethers such as dioxane, diethyl ether, tetrahydrofuran, glycol monomethyl ether, Glycol dimethyl ether or glacial acetic acid, dimethylformamide, Dimethyl sulfoxide, acetonitrile, pyridine and hexamethylphosphoric acid triamide.

The reaction temperatures can be varied over a wide range. In general, between 20 and 150 ^° C., preferably between 20 and 100 ^° C., in particular at the boiling point of the respective solvent.

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-VZ-

The reaction can be carried out under normal pressure, but also under increased pressure. Generally works one under normal pressure.

When carrying out the method according to the invention as one mole of the ylidene-ß-keto ester of the formula (VI) with one mole of the enaminocarboxylic acid ester of the formula (VII) reacted in a suitable solvent.

Process variant D

According to method D, a ylidene-ß-ketoester of the general Formula (VI)

4th
CO-R

R-CH = C (VI)

COR ³

with an amine of the formula (IV). and a ß-ketocarboxylic acid ester the general

R ⁵ -NH ₂ , R ² -CO-CH ₂ -CO ₂ R ¹

(IV) (VIII)

Formula (VIII) brought to reaction.

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S3

Examples of the ylidene-β-ketoesters of the formula (VI) used as starting compounds are already under Process variant C listed.

The amines of the formula (IV) which can be used according to the invention are already described under process variant B.

The ß-ketocarboxylic acid esters used as starting materials of the formula (VIII) are known from the literature or can be prepared by methods known from the literature Become (e.g. D * Borrmann, "Implementation of Diketen mit Alcohols, phenols and mercaptans ", in Houben-Weyl, Methods of Organic Chemistry, Vol. VII / 4, 230 ff (1968); Y. Oikawa, K. Sugano, and O. Yonemitsu, J. Org. Chem. J43, 2087 (1978)).

Examples are:

Methyl acetoacetate, Ethyl acetoacetate, hexyl acetoacetate, octyl acetoacetate, Decyl acetoacetate, tetradecyl acetoacetate, Isopropyl acetoacetate, neopentyl acetoacetate, Cyclopentyl acetoacetate, allyl acetoacetate, Acetoacetic acid (2-methoxyethyl) ester, Acetoacetic acid (2.2.2-trifluoroethyl) ester,

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- 3 * 1 -

Acetoacetic acid (2-chloroethyl) ester, acetoacetic acid (2-cyanoethyl) ester, acetoacetic acid (2-acetoxyethyl) ester, acetoacetic acid benzyl ester,
Acetoacetic acid (2-phenylethyl) ester, acetoacetic acid (2-phenoxyethyl) ester, acetoacetic acid (2-dimethylaminoethyl) ester, acetoacetic acid (2-N-benz.yl-N-methyl-aminoethyl) ester, Ethyl propionylacetate,
0 decyl propionylacetate

All inert organic solvents are suitable as diluents. These preferably include Alcohols such as ethanol, methanol, isopropanol, ethers such as dioxane, diethyl ether, tetrahydrofuran, glycol monomethyl ether, Glycol dimethyl ether or glacial acetic acid, dimethylformamide, dimethyl sulfoxide, acetonitrile, Pyridine and hexamethyl phosphoric acid triamide.

The reaction temperatures can be varied over a wide range. In general, between 20 and 150 ^° C., in particular between 40 and 120 ^° C., but preferably at the boiling point of the solvent in question.

The reaction can be carried out under normal pressure, but also under increased pressure. Generally works one under normal pressure.

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ss

- 3-5 -

When carrying out the method according to the invention the substances of the formula (VI) / (IV) and (VIII) involved in the reaction are used in each case in molar amounts. The amine used is expediently added in an excess of 1 to 2 mol.

Process variants E and F

According to method E and F, an aldehyde of the formula '(IX)

R-C (IX)

either (Method E) with an enaminocarboxylic acid ester of formula (III) and one

R ³ HZ-CH-CO ₉ R ⁴ , R ² -CO-CH ₉ -CO ₉ R ¹

R NH

(III) (VIII)

ß-ketocarboxylic acid ester of the general formula (VIII)

or (method F) with an enaminocarboxylic acid ester

of the general formula (VII)

R ² -C = CH-CO ₉ R ¹ , ■ R ³ -CO-CH ₉ -CO R ⁴ R NH

(VII) (V)

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and a ß-ketocarboxylic acid ester of the general formula (V) reacted.

The enaminocarboxylic acid esters which can be used according to the invention of the general formulas (III) and (VII) have already been given under process variants A and C. The ß-ketocarboxylic acid esters of the general formulas (VIII) and (V) which can be used according to the invention were already described under process variants D and B.

The aldehydes of the formula used as starting materials (IX). are known from the literature or can be prepared by methods known from the literature (cf. e.g. . E. Mosettig, Org. Reactions VIII, 218 ff (1954)).

Examples are:

Benzaldehyde, 2-, 3- or 4-phenybenzaldehyde, - or ß-naphthylaldehyde, 2-, 3- or 4-methylbenzaldehyde, 2- or 4-n-butybenzaldehyde, 2-, 3- or 4-isopropylbenzaldehyde, 2- or 4-cyclopropybenzaldehyde, 2,3-tetramethylene benzaldehyde, 3,4-dioxymethylene benzaldehyde, 2-, 3- or 4-methoxybenzaldehyde, 2-cyclopropylmethyloxybenzaldehyde, 2-, 3- or 4-chlorine / bromine / fluorobenzaldehyde, 2-, 3- or 4-trifluoromethylbenzaldehyde, 2-, 3- or 4-trifluoromethoxybenzaldehyde, 2-, 3- or 4-difluoromethoxybenzaldehyde, 2-, 3- or 4-nitrobenzaldehyde, 2-, 3- or 4-cyanobenzaldehyde, 3-azidobenzaldehyde, 2-, 3- or 4-methylthiobenzaldehyde,

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- 3-7 -

2-, 3- or 4-Methylsulfiny! .Benzaldehyd, 2-, 3-, or 4-Methylsulfonylbenzaldehyd, 2,3-, 2,4- or 2,6-dichlorobenzaldehyde, 2-fluoro-3-chlorobenzaldehyde, 2,4-dimethyl-benzaldehyde, 2,4- or 2,6-dinitrobenzaldehyde, 2-chloro-6-nitrobenzaldehyde, 4-chloro-2-nitrobenzaldehyde, 2-nitro-4-methoxybenzaldehyde, 2-nitro-4-cyanobenzaldehyde, 2 ^ - chloro-4-cyanobenzaldehyde, 4-cyano-2-methy! Benzaldehyde, 3-methyl-4-trifluoromethylbenzaldehyde, 3-chloro-2-trifluoromethylbenzaldehyde, Thiophene-2-aldehyde, furan-2-

.10 aldehyde, pyrrole-2-aldehyde, pyrazole-4-aldehyde, imidazole-2-aldehyde, Oxazole-2-aldehyde, isoxazole-3-aldehyde,. Thiazol-2-aldehyde, pyridine-2-, 3- or 4-aldehyde, 6-methyl-pyridine-2-aldehyde, 2-methylthio-pyridine-3-aldehyde, indole-3-aldehyde, benzimidazole-2-aldehyde, benzoxazole-4-aldehyde, Benzoxadiazole-4-aldehyde, quinoline-4-aldehyde, Quinazoline-2-aldehyde, quinoxaline-5-aldehyde ..

All inert organic solvents are suitable as diluents. These preferably include Alcohols such as ethanol, methanol, isopropanol, ethers such as dioxane, diethyl ether, tetrahydrofuran, glycol monomethyl ether, Glycol dimethyl ether or glacial acetic acid, dimethylformamide, Dimethyl sulfoxide, acetonitrile, pyridine and hexamethylphosphoric acid triamide.

The reaction temperatures can be varied over a wide range. In general carried out between 20 and 15O ⁰ C, but preferably at the boiling point of the respective solvent.

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se

- 38 -

The reaction can be carried out under normal pressure, but also under increased pressure. Generally works one under normal pressure.

When carrying out the method according to the invention the substances involved in the reaction are used in molar amounts.

Process variant G

In the event that X in the general formula I is NH

2 3

and R or R represents an amino group, it has been found that the compounds according to the invention are when you get

either

Ylidene-ß-ketoester of the general formula (II)

CO ₂ R ^{1 H} 2 ^N \

R-CH = C, C = CH-CO ₂ R ⁴

COR ² H ₂ N

(II) (X)

with amidinoacetic acid esters of the general formula (X) or

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sy

Ylidene-ß-ketoester of the general formula (VI)

CO ₂ R ^H 2 ^N \

R-CH = C, C = CH-CO-R ¹

COR ^H 2 ^N

(VI) (XI)

with amidinoacetic acid esters of the general formula (XI) to react.

The ylidene-ß-ketoesters which can be used according to the invention General formulas (II) and (VI) have already been described under process variant A and C, respectively.

The amidinoacetic acid esters of the formula (X) used as starting substances are new, but can be prepared by methods known from the literature (cf., for example, H. Meyer, F. Bossert and H. Horstmann, Liebigs Ann. Chem. 1977 , 1895).

Examples are:

Heptyl amidinoacetate,
5 octyl amidinoacetate,
Amidinoacetic acid decyl ester,
Amidinoacetic acid undecyl ester,
Amidinoacetic acid dodecyl ester,
Amidinoacetic acid tetradecyl ester,

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-4U-

Amidinoacetic acid (2-pentoxyethyl) ester, amidinoacetic acid (2-heptyloxyethyl) ester / Amidinoacetic acid (u9-chlorodecyl) ester, ■ Amidinoacetic acid (CJ -acetoxydecyl) ester.

The amidinoacetic acid esters of the formula (XI) used as starting substances are or can be known from the literature be produced by known methods (cf. e.g. H. Meyer, F. Bossert and H. Horstmann, Liebigs Ann. Chem. 1977, 1895).

Examples are:

Amidinoacetic acid decyl ester, Amidinoacetic acid tetradecyl ester, Amidinoacetic acid (2-methoxyethyl) ester, amidinoacetic acid (2-propoxyethyl) ester, 5 amidinoacetic acid (2-chloroethyl) ester, Amidinoacetic acid benzyl ester, amidinoacetic acid (2-phenoxyethyl) ester, Amidinoacetic acid (2-dimethylaminoethyl) ester, amidinoacetic acid (2-N-benzyl-N-methyl-aminoethyl) ester, Isopropyl amidinoacetate ,.

Amidinoacetic acid cyclopentyl ester.

The amidines can be used either in free form or in the form of their salts (e.g. hydrohalides) will. They are released from the salts with basic agents (e.g. alkali alcoholates).

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All inert organic solvents are suitable as diluents. These preferably include
Alcohols such as methanol, ethanol, propanol; Ether like
Dioxane diethyl ether or glacial acetic acid, pyridine, dimethylformamide, dimethyl sulfoxide or acetonitrile.

The reaction temperatures can be varied over a wide range. Generally one works
between 20 and 25O ⁰ C, preferably at the boiling point of the solvent.

The reaction can be carried out under normal pressure, but also under increased pressure. Generally works one at normal pressure. '

When carrying out the method according to the invention the substances involved in the reaction are used in molar amounts.

Process variant H

In the event that X in the general formula (I) for N-R, where R has the meaning given above,

2 3

and R or R represents the hydroxymethyl group, it has proven advantageous to use the corresponding

2 3
Compounds according to the invention in which R or R

stands for acetoxymethyl, subject to the conditions of an acidic or basic hydrolysis.

Le A 21 533

The main acids are hydrogen halide acids, Acetic acid or ammonium chloride in question, the bases have proven to be alkali and alkaline earth carbonates proved beneficial.

As a diluent come water and all with water miscible inert organic solvents in question. These preferably include alcohols such as methanol or Ethanol, ethers such as tetrahydrofuran or ethylene glycol dimethyl ether, Glacial acetic acid, pyridine, dimethylformamide, dimethyl sulfoxide or acetonitrile.

The reaction temperatures can be varied over a wide range. Generally one works between 0 and 100 ° C, preferably at room temperature.

Process variant I

In the event that X is in the general formula (I)

2 3

Represents oxygen atom and R or R represents an amino group is, it has been found that the compounds according to the invention are obtained if

either
Ylidene-ß-ketoester of the general formula (II)

R-CH = C, N = C-CH ₀ -CO ₉ R ⁴

\ 2

COR

(II) (XII)

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-VS-

with cyanoacetic acid esters of the general formula (XII)

or

Ylidene-ß-ketoester of the general formula (VI)

.CO ₂ R

R-CH = C, N = C-CH ₉ -CO ^ R ¹

^ \ 3

COR

(VI) (XIII)

with cyanoacetic acid esters of the general formula (XIII) to react.

The ylidene-ß-ketoesters which can be used according to the invention General formulas (II) and (VI) have already been described under process variant A and C. ·

The cyanoacetic acid esters of the formulas (XII) and (XIII) used as starting substances are known or are known can be represented by methods known from the literature (see Org. Syntheses, Collect. Vol. I, p. 254 (1958)).

Examples are:

Ethyl cyanoacetate,
Butyl cyanoacetate,
Cyanoacetic acid heptyl ester,

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Cyanoacetic acid decyester, Undecyl cyanoacetate, tetradecyl cyanoacetate, isopropyl cyanoacetate, Cyclopentyl cyanoacetate, benzyl cyanoacetate, Cyanoacetic acid (2-methoxyethyl) ester, Cyanoacetic acid (2-propoxyethyl) ester, Cyanoacetic acid (2-pentyloxyethyl) ester, 2-phenoxyethyl cyanoacetate, 2.2.2-trifluoroethyl cyanoacetate, Cyanoacetic acid (2-acetoxyethyl) ester, Cyanoacetic acid (2-dimethylaminoethyl) ester, cyanoacetic acid (2-N-benzyl-N-methyl-aminoethyl) ester.

The reaction is preferably carried out in the presence of basic catalysts such as piperidine.

All inert organic solvents are suitable as diluents. These preferably include Alcohols such as ethanol, methanol, isopropartol, ethers such as dioxane, diethyl ether, tetrahydrofuran, glycol monomethyl ether, Glycol dimethyl ether, dimethylformamide, Dimethyl sulfoxide, acetonitrile, pyridine and hexamethylphosphoric acid triamide.

The reaction temperatures can be varied over a wide range. In general carried out between 20 and 15O ⁰ C, but preferably at the boiling point of the respective solvent.

Le Ä 21 533

The reaction can be carried out under normal pressure, but also under increased pressure. Generally works one under normal pressure.

When carrying out the method according to the invention are the substances involved in the reaction in the presence of a basic catalyst in each case in molar Amounts used.

The above manufacturing methods are only given for clarity, and the preparation of the compounds of formula (I) is not limited to this process limited, but any modification of this process is equally applicable to the manufacture of the compounds according to the invention applicable.

Depending on the choice of starting substances, the inventive Compounds exist in stereoisomeric forms, which are either like image and mirror image (Enantiomers) or which do not behave like image and mirror image (diastereomers). Both the Antipodes and the race forms as well as the diastereomer mixtures are the subject matter of the present invention Invention. The racemic forms, like the diastereomers, can be converted into the stereoisomer in a known manner separate uniform components (see e.g. E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).

In addition to the preparation examples listed below, the following active ingredients according to the invention may be mentioned:

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- 46 -

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) -pyridine * -3, 5-dicarboxylic acid heptyl-methyl-ester

1,4-Dihydro-2 _/ 6-dimethyl-4- (2-nitrophenyl) -pyridine-3,5-dicarboxylic acid decyl-ethyl-ester

1 ^ -Duhydro ^ fö-dimethyl ^ - (2-nitrophenyl) -pyridine-3,5-dicarboxylic acid methyl undecyl ester

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) -pyridine-3,5-dicarboxylic acid heptyl-tetradecyl-ester

- (2-nitrophenyl) pyridine-3, 5 TO dicarboxylic acid decyl (2.2.2-trifluoroethyl) ester

2-Amino-1,4-dihydro-6-methyl-4- (2-nitrophenyl) pyridine 3, S-dicarboxylic acid-S-decyl-δ-ethyl ester

1,4-dihydro-2,6-dimethyl 1-4- (3-nitrophenyl) pyridine-3,5 dicarboxylic acid ethy1-hepty1-ester

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid decyl (2.2.2-trifluoroethyl) ester

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid (2-N-benzyl-N-methyl-aminoethyl) -decyl-ester

1,4-Dihydro-2-hydroxymethyl-6-methyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid-2-decyl-5-ethyl-ester

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1, ^ dihydro ^ -hydroxymethyl-e-ynethyl · ^ - (3-nitrophenyl) ■ pyridine-3,5-dicarboxylic acid 2-decyl-5-ethyl ester

1,4-Dihydro-2,6-dimethyl-4- (pyridyl-3) -pyridine-3,5-dicarboxylic acid decyl-ethyl ester

1,4-Dihydro-2,6-dimethyl-4- (2.1.3-benzoxadiazolyl-4) -pyridine-3 , S-dicarboxylic acid decyl-ethyl-ester

1,4-Dihydro-2,6-dimethyl-4- (2-cyanophenyl) -pyridine-3,5-dicarboxylic acid decyl-ethyl-ester

1 _/ 4-dihydro-2,6-dimethyl-4- (2-trifluoromethoxyphenyl) -pyridine-3, S-dicarboxylic acid decyl-ethyl-ester

^ - (2-methoxyphenyl) -pyridine-3, S-dicarboxylic acid decyl-ethyl-ester

1,4-Dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) -pyridine-3,5-dicarboxylic acid decyl-ethyl-ester

1,4-Dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) pyridine-3,5-dicarboxylic acid decyl (2.2.2-trifluoroethyl) ester

1 _/ 4-dihydro-2 _/ 6-dimethyl-4- (2-trifluoromethylphenyl) -pyridine-3, S-dicarboxylic acid methyl undecyl ester

The new compounds have a broad and varied range of pharmacological effects; with surprising long duration of action.

Le A 21 533

In particular, the following main effects could be demonstrated in animal experiments:

1. The compounds cause parenteral, oral ' and perlingual addition a clear and long-lasting Expansion of the coronary vessels. This effect on the coronary vessels is caused by a Simultaneous' nitrite-like heart-relieving effect intensified.

They influence or change the heart metabolism in the sense of saving energy.

2. The excitability of the stimulation and excitation conduction system within the heart is reduced, so that an anti-fibrillation effect which can be demonstrated in therapeutic doses results.

3. The smooth muscle tone of the vessels is greatly reduced under the action of the compounds. This vasospasmolytic effect can take place in the entire vascular system, or more or less isolated in circumscribed vascular areas (such as the central nervous system). The compounds are therefore particularly suitable as cerebral therapeutics.

4. The compounds lower blood pressure from normotensive and hypertensive animals and can thus be called. antihypertensive agents are used.

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- Jt9 -

5. Connections have strong muscular-spasmol'ytisehe Effects / those on the smooth muscles of the stomach, intestinal tract, urogenital tract and respiratory system become clear.

The compounds according to the invention are suitable due to these properties especially for the prophylaxis and therapy of acute and chronic ischemic heart disease in the broadest sense, for the therapy of high pressure and for the treatment of cerebral and peripheral circulatory disorders.

The new active ingredients can be converted into the usual formulations in a known manner, such as tablets, Capsules, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, among Use of inert, non-toxic pharmaceutically suitable carriers or solvents. Here should the therapeutically active compound in a concentration of about 0.5 to 90 wt .-% of the Total mixture must be present, i.e. in amounts sufficient to cover the stated dosage range to reach.

The formulations are produced, for example, by extending the active ingredients with solvents and / or carriers, optionally using of emulsifiers and / or dispersants, e.g. in the case of the use of water as a diluent organic solvents can optionally be used as auxiliary solvents.

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Examples of auxiliaries are:

Water, non-toxic organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. Peanut / sesame oil), alcohols (e.g. ethyl alcohol, GIy- ' cerin), glycols (e.g. propylene glycol, polyethylene glycol), solid carriers such as natural rock flour (e.g. kaolins, clays, talc, chalk), synthetic Rock flour (e.g. highly dispersed silicic acid, silicates), sugar (e.g. raw, milk and grape sugar), Emulsifiers (e.g. polyoxyethylene fatty acid esters, .Polyexyethylene fatty alcohol ethers, alkyl sulfonates and Aryl sulfonates), dispersants (e.g. lignin, sulfite waste liquors, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The application takes place in the usual way, preferably orally or parenterally, especially perlingually or intravenously. In the case of oral use you can Tablets, of course, in addition to the carriers mentioned, also include additives such as sodium citrate and calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably potato starch, gelatin and the like. Farther Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting will. In the case of aqueous suspensions and / or elixirs intended for oral use, can use the active ingredients except with the above

Le A 21 533

Excipients with various flavor enhancers or dyes are added.

In the case of parenteral use, solutions of the active ingredients can be made using suitable liquid Support materials are used.

In general, it has been found to be advantageous in the case of intravenous administration, amounts of about 0.001 to 10 mg / kg, preferably about 0.05 to 5 mg / kg of body weight to be administered per day to achieve effective results, and for oral administration is the Dosage about 0.05 to 20 mg / kg, preferably 0.5 to 5 mg / kg of body weight per day.

Nonetheless, it may be necessary to deviate from the amounts mentioned, depending on the amount on the body weight of the test animal or the type of application route, but also on the basis of the Animal species and their individual behavior towards the drug or the type of its formulation and the time or interval at which the administration takes place. So it may be sufficient in some cases be able to manage with less than the aforementioned minimum amount, while in other cases the aforementioned upper limit must be exceeded. In the case of the application of larger amounts, it can be recommended be to distribute these in several individual doses over the day. For application in human medicine the same dosage range is provided. The above statements also apply accordingly.

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Manufacturing examples example 1

1,4-Dihydro-2,6-dimethyl 1-4- (2-nitrophenyl) pyridine-3,5-d-carboxylic acid decyl-ethyl ester

O,

CO ₉ - (CH ₉ ) -CH, g

A solution of 263 g (1 mol) of 2- (3-nitrobenzylidene) ethyl acetate and 241 g (1 mol) of 3-aminocarboxylic acid decyl ester in 2.4 l abs. Ethanol was heated to boiling under nitrogen for 18 hours. It was then filtered hot and concentrated to about half the volume in vacuo. The concentrated solution was ice-cooled, a thick slurry of crystals precipitating out. This was suction filtered, recrystallized from ethanol and, after washing with 0.5 1 hexane η dried in a vacuum oven at 6O ⁰ C.

Melting point: 106-108 ⁰ C
Yield: 337 g (69.5%)

Example 2

H ₃ CO ₂ C

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- S3 -

Analogously to Example 1, the 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5 was obtained by reacting 2- (3-nitrobenzylidene) -acetoacetic acid methyl ester and 3-aminocarboxylic acid octyl ester in ethanol obtained -dicarbonsäuremethyl-octyl-ester, mp. 100 ⁰ C (ethanol). Yield: 65% of theory

Example 3

Analogously to Example 1, by reacting 2- (3-nitrobenzylidene) -acetoacetic acid ethyl ester and 3-aminocarboxylic acid octyl ester in ethanol of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid ethyl-octyl ester obtained with a melting point of 82 ° C (methanol). Yield: 61% of theory

Example 4

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Analogously to Example 1, the 1,4-dihydro-2,6-dimethy1-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid isopropyl-octyl was obtained by reacting 2- (3-nitrobenzylidene) -acetoacetic acid isopropyl ester in ethanol esters obtained, mp. 70 ⁰ C (methanol).

Yield: 65% of theory

Example 5

H ₃ CO ₂ C

Analogously to Example 1, methyl 2- (3-nitrobenzylidene) -acetoacetate was converted with 3-aminocarboxylic acid decyl ester in ethanol of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid decyl methyl ester obtained from m.p. 90 ° C (ethanol). Yield: 73% of theory

Example 6

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- 5 *} -

Analogously to Example 1, by reacting 2- (3-nitrobenzylidene) -acetoacetic acid- (2-chloroethyl) ester with 3-. Aminocrotonic acid decyl ester in ethanol of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid (2-chloroethyl) decyl ester, melting point: 124 ° C (ethanol ) obtain.
Yield: 65% of theory

Example 7

Analogous to example 1 was by reaction of 2- (2-chlorobenzylidene) -acete'ssigsäureethylester with 3-Aminocrotonsäuredecylester in ethanol of 1,4-dihydro-2,6-dimethyl-4- (2-chlorophenyl) -pyridine-3,5-dicarboxylic acid decyl-ethyl ester of m.p .: 72 ° C (methanol) obtained.

Yield: 58% of theory.

Ex iel 8

CF ₃

^CO 2 ^C 10 ^H 21 ⁽ⁿ⁾
CH_

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- 56 -

Analogously to Example 1, the 1,4-dihydro-2,6-dimethyl-4- (2-trifluoromethylphenyl) -pyridine-3,5 was obtained by reacting 2- (2-trifluoromethylbenzylidene) -acetoacetic acid ethyl ester with 3-aminocrotonic acid decyl ester in ethanol obtained -dicarbonsäuredecyl ethyl ester, mp .: 76 ⁰ C (methanol). Yield: 52% of theory

Example 9

Analogously to example 1, by reaction of 2- (3-nitrobenzylidene) -acetoacetic acid isopropyl ester with 3-aminocrotonic acid decyl ester in ethanol of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid decyl isopropyl ester of m.p .: 99 ° C (ethanol) obtained. Yield: 6 9% of theory

Example 10

NO,

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Analogously to Example 1, methyl 2- (3-nitrobenzylidene) -acetoacetate was converted with 3-aminocrotonic acid undecyl ester in ethanol of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid methyl-undecyl-ester of m.p .: 85 ° C (ethanol) obtained. Yield: 78% of theory

Example 11

^CO 2 ^C 11 ^H 23 ⁽ⁿ »

CH

Analogously to Example 1, the 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3, 5-dicarbonsäureethyl-undecyl-ester was obtained, mp .: 107 ⁰ C (ethanol). Yield: 75% of theory

Example 12

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Analogously to Example 1, the 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid isopropyl was obtained by reacting 2- (3-nitrobenzylidene) -acetoacetic acid isopropyl ester with 3-aminocrotonic acid undecyl ester in ethanol obtained undecyl ester, mp .: 108 ⁰ C (ethanol). Yield: 6 9% of theory

Example 13

H ₃ CO ₂ C

HC N CH
H

Analogously to Example 1, the 1,4-dihydro-2,6-dimethy1-4- (3-nitrophenyl) -pyridine-3,5-d ! carboxylic acid dodecyl methyl ester of melting point: 94 ⁰ C (ethanol) obtained. Yield: 6-6% of theory

Example 14

H ₅ C ₃ O ₂ C

Le A 21 533

Analogously to Example 1, the 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid dodecyl was obtained by reacting ethyl 2- (3-nitrobenzylidene) -acetoacetate with dodecyl 3-aminocrotonate in ethanol -ethyl ester of Pp .: 100 ⁰ C (ethanol) obtained. Yield: 76% of theory

example 15th I. H ₃ C O " ^N0 2 (l ΙΪ .CO ₂ > - N
H ^ CH ₃

(n)

Analogously to Example 1, the 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid dodecyl was obtained by reacting 2- (3-nitrobenzylidene-acetoacetic acid isopropyl ester with 3-aminocrotonic acid dodecyl ester in ethanol obtained isopropyl ester, mp .: 100 ⁰ C (ethanol), yield: 60% of theory

Example 16

(n)

Le A 21 533

- EJPf -

Analogously to example 1, by reaction of 2- (3-nitrobenzylidene) -acetoacetic acid isopropyl ester with 3-aminocrotonic acid (2-pentyloxyethyl) - »ester in isopropanol of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid-isopropyl- (2-pentyloxyethyl) -ester of melting point: 75 ° C (ether / petroleum ether) obtained. Yield: 65% of theory

Example 17

(η)

Analogously to example 1, by reaction of 2- (3-nitrobenzylidene) -acetoacetic acid isopropyl ester with 3-aminocrotonic acid (2-hexyloxyethyl) ester in isopropanol der 1,4-Dihydro-2,6-dimethyl 1-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid (2-hexyloxyethyl) isopropyl ester of melting point: 83 ° C. (ether / petroleum ether). Yield: 80% of theory

Example 18

NO.

CO ₂ CH ₂ CH ₂ -OC ₇ H ₁₅

CH.

Le A 21 533

<y

- 6Ί -

Analogously to Example 1, the 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) was obtained by reacting 2- (3-nitrobenzylidene) -acetoacetic acid isopropyl ester with 3-aminocrotonic acid (2-heptyloxyethyl) ester in isopropanol. pyridine-3,5-dicarboxylic acid (2-heptyloxyethyl) isopropyl ester obtained, mp .: 80 ⁰ C (ether / petroleum ether). Yield: 72% of theory

Example 19

Analogously to Example 1 by reaction of 2- (3-nitrobenzylidene) -acetessigsäureisopropylester with 3-Aminocrotonsäure- (2-octyloxyethyl) ester in isopropanol of 1,4-dihydro-2, 6-dimethy1-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid isopropyl- (2-octyloxyethyl) esters obtained, mp .: 89 ⁰ C (ether / petroleum ether). Yield: 76% of theory

Example 20

2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid 5-decyl-3-ethyl ester

Le A 21 533

- 92 -

CO ₂ C ₂ H ₅

In a solution of 18.8 g (50 mmol) of 2- (3-nitrobenzylidene) -acetoacetic acid decyl ester and 8.3 g (50 mmol) of amidinoacetic acid ethyl ester hydrochloride in 250 ml of ethanol, a solution of 1.15 g was added with stirring and at room temperature (50 mmol) of sodium in 100 ml of ethanol were added dropwise. The mixture was then heated to boiling for 15 minutes. After standing overnight, the precipitated sodium chloride was filtered off / the filtrate was concentrated in vacuo and the oily residue was crystallized by trituration with ether / petroleum ether. The crude product was filtered off and recrystallized from ethanol, m.p .: 190-191 ⁰ C. Yield: 6% of theory 5

Example 21

5 2-Amino-6-methyl-4- (3-nitrophenyl) -4H-pyran-3, 5-dicarboxylic acid 5-decy1-3-ethyl ester

CO ₂ C ₂ H ₅

Le A 21 533

A solution of 5.7 g (15 mmol) of 2- (3-nitrobenzylidene) decyl acetate and 1.8 g (15 mmol) of ethyl cyanoacetate in 15 ml of ethanol was heated to boiling in the presence of 0.3 ml of piperidine for 4 hours. The solvent was then distilled off and the oily residue was _{crystallized after purification by column chromatography (SiO 2} , chloroform), melting point: 100 ^° C., yield: 3.3 g (45%)

Le A 21 533

Claims (10)

Claims in which R for aryl or for thienyl, furyl, pyryl, pyrazolyl, Imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, Indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, quinolyl, isoquinolyl, Quinazolyl or quinoxalyl is where in the case of the aryl radical and the heterocycles, optionally 1 to 2 identical or different substituents from the group phenyl, alkyl, alkoxy, alkylene, dioxymethylene, halogen, trifluoromethyl ^ Polyfluoroalkoxy, nitro, cyano, azido or SO - Contain alkyl (m = 0 to 2), R for a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon Substance rest, which may be interrupted by 1 oxygen atom in the chain, and / or which is optionally substituted Le A 21 533 by halogen, cyano, hydroxy, acyloxy, phenyl, Phenoxy, or an amino group, which in turn has 2 identical or different substituents is substituted from the group alkyl, aryl or aralkyl, R for a straight-chain, branched or cyclic, saturated or unsaturated aliphatic hydrocarbon radical with 7 to 14 carbon atoms stands, which is optionally interrupted by an IQ oxygen atom, and / or the optionally by halogen, hydroxy or acyloxy is substituted, R and R are identical or different and each represent hydrogen, a straight-chain or a different A branched alkyl radical, an aryl radical or an aralkyl radical, or in the event that one of the substituents 2 3
R or R has the abovementioned meaning, the other being hydroxymethyl, acetoxymethyl or amino and X is N-R, where R is hydrogen, a straight-chain or branched alkyl radical, optionally interrupted by an oxygen atom, a morpholinoalkyl radical, an aryl radical or an aralkyl radical or Le A 21 533 X stands for an oxygen atom if at least one d
indicates 2 3
one of the radicals R or R is an amino group and their pharmaceutically acceptable acid addition salts. 2. Compounds of the general formula (I) according to claim 1, in which R for phenyl, naphthyl or for thienyl, furyl, pyryl, Pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, Benzoxadiazolyl, quinolyl, isoquinolyl, quinazolyl. Or quinoxal, the named Ring systems in each case by 1 or 2 identical or different substituents from the group Phenyl, straight-chain or branched alkyl with 1 to 8 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, alkoxy with 1 to 4 carbon atoms, tri-, tetra- and pentamethylene, dioxymethylene, Halogen, trifluoromethyl, trifluoromethoxy, Difluoromethoxy, tetrafluoroethoxy, nitro, Cyano, azido or SO-alkyl, in which m is a number from 0 to 2 and alkyl is preferably 1 to Contains 4 carbon atoms, may be substituted, Le A 21 533 R for a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical with up to 20 carbon atoms, which is optionally replaced by 1 oxygen atom is interrupted in the chain and / or which is optionally substituted by halogen, cyano, Hydroxy, acetoxy, phenyl, phenoxy or an amino group, which in turn is represented by 2 identical or different Substituents from the group consisting of alkyl having 1 to 4 carbon atoms, phenyl or benzyl is substituted, R stands for a straight-chain, branched or cyclic, saturated or unsaturated aliphatic Hydrocarbon radical with 7 to 14 carbon atoms stands, if necessary by a Oxygen atom in the chain is interrupted and / or optionally by halogen, hydroxy or acetoxy is substituted, 3
R and R are identical or different and each represent hydrogen, a straight-chain or branched one Alkyl radical with up to 4 carbon atoms, one Phenyl radical or a benzyl radical, 2 3 or one of the substituents R or R represents a hydroxymethyl, acetoxymethyl or amino group, the other substituent having the meaning given above,
and Le A 21 533 X represents NR wherein R represents hydrogen, a 'straight or branched _r optionally interrupted by an oxygen atom alkyl radical having up to 4 carbon atoms, a Morpholinoacetylrest, a phenyl radical or a benzyl radical, is,
or stands for an oxygen atom, in which case one of the substituents
means. 2 3 Substituents R or R always an amino group 3. Compounds of general formula (I) according to claim 1, in which R is phenyl, pyridyl, thienyl or furyl, where the phenyl ring optionally by a ■ ^ 5 or two identical or different substituents ducks from the group phenyl, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 2 carbon atoms, Fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, difluoromethoxy, nitro, cyano, Azido or alkyl mercapto with 1 to 4 coals Substance atoms in the alkyl radical are substituted, R is a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon The remainder with up to 14 carbon atoms is optionally represented by an oxygen atom is interrupted and / or which is optionally substituted by fluorine, chlorine, Cyano, hydroxy or amino, Le A 21 533 R for a straight, branched or cyclic / saturated or unsaturated aliphatic Hydrocarbon radical with 7 to 12 carbon atoms, which optionally by an oxygen atom in the chain below is broken and / or which is optionally substituted by fluorine, chlorine, hydroxy or acetoxy is, 3
R and R are identical or different and each represent hydrogen, alkyl having 1 to 2 carbon atoms, phenyl or benzyl, or 2 3 one of the substituents R or R for a hydroxymethyl, acetoxymethyl or amino group stands, with the other substituent the previous has given meaning, X stands for N-R, where R stands for hydrogen, an alkyl radical with up to 4 carbon atoms or optionally is interrupted by an oxygen atom, a morpholine alkyl radical with 1 to 4 carbon atoms in the alkyl part, one phenyl radical or a benzyl radical, or stands for an oxygen atom, in which case one of the substituents]
group means. Le A 21 53 3 2 3
the substituents R or R always have an amino 320862S 7 4. Compounds of general formula (I) according to claim 1, in which R stands for a phenyl radical, one or two identical or different substituents from the group consisting of chlorine, trifluoromethyl, nitro or Contains cyano, or represents a benzoxadiazolyl radical, R is a straight-chain or branched carbon hydrogen residue with up to 7 carbon atoms represents, possibly by a sour atom in the chain is interrupted and / or optionally by fluorine or chlorine or an amino group is substituted, in turn by two methyl groups or by one Methyl and a benzyl group may be substituted can, R is a straight-chain, branched or cyclic, saturated or unsaturated aliphatic Hydrocarbon residue with seven to twelve carbon atoms means given possibly through an oxygen atom in the chain is interrupted or which is optionally substituted by fluorine, chlorine or hydroxyl, R ² and R ³ each represent hydrogen or an alkyl radical having 1 to 2 carbon atoms, Le A 21 533 - 71 - 2 3
■ Or one of the substituents R or R for the Amino group, where the other substituent has the meaning given above, and X stands for N-R, where R is a hydrogen atom or represents an alkyl radical with up to 3 carbon atoms, or stands for an oxygen atom, where one of the substituents
represents. 2 3
Substituents R or R always an amino group 5. Compounds of the general formula (I) according to claim 1, in which R is a straight-chain, branched or cyclic saturated or unsaturated alipha- ■ ^ 5 tables of hydrocarbon residue with 10 coals Means substance atoms, which may be interrupted by an oxygen atom in the chain or which is optionally substituted by fluorine, chlorine or hydroxyl, and 0 the other substituents, which in claim 2 have given meaning. 6. Process for the preparation of compounds of the general Formula (I) Le A 21 533 (I) in which R for aryl or for thienyl, furyl, pyryl, pyrazolyl, Imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, Indolyl, benzimidazolyl, benzoxazolyl., Benzisoxazolyl, benzoxadiazolyl, quinolyl, isoquinolyl, Quinazolyl or quinoxalyl, the aryl radical and the heterocycles optionally 1 to 2 identical or different substituents from the group phenyl, alkyl, alkoxy, Alkylene, dioxymethylene, halogen, trifluoromethyl, Polyfluoroalkoxy, nitro, cyano, azido or SO-alkyl (m = 0 to 2) contain, R for a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon Substance rest, which may be interrupted by 1 oxygen atom in the chain, and / or which is optionally substituted by halogen, cyano, hydroxy, acyloxy, phenyl, Phenoxy, or an amino group, which in turn has 2 identical or different substituents Le A 21 533 - vs - substituted from the group consisting of alkyl, aryl or aralkyl is, R stands for a straight-chain, branched or cyclic, saturated or unsaturated aliphatic Hydrocarbon residue with 7 to 14 coals material atoms, which is optionally interrupted by an oxygen atom, and / or the is optionally substituted by halogen, hydroxy or acyloxy, 3
R and R are the same or different and each represents hydrogen, a straight-chain or branched alkyl radical, an aryl radical or a Aralkyl radical, or in the event that one of the substituents R or R has the abovementioned meaning, the other is hydroxymethyl, acetoxymethyl or amino
and . X stands for N-R, where R stands for hydrogen, a straight or branched chain, optionally alkyl radical interrupted by an oxygen atom, a morpholinoalkyl radical, an aryl radical or an aralkyl radical or Tc X stands for an oxygen atom if at least 2 3 one of the radicals R or R is an amino group, Le A 21 533 and their pharmaceutically acceptable acid addition salts, characterized in that in the event that X in the general formula (I) represents NR stands and 2 '3' R and R each represent hydrogen, a straight chain or branched alkyl radical, an aryl radical, an aralkyl radical or for the acetoxymethyl group stand, A) Ylidene-ß-ketoester of the general formula (II) CO ₉ R ₁ P-CTT-C
R-CH-C ~, ^ - COR in which 1 2 '
R, R and R have the meaning given above, with enaminocarboxylic acid esters of the general formula (III) R ³ '-C = CH-CO ₉ R ⁴ (III) 5 '
R NH in which 31 5 4
R, R and R have the meaning given above, optionally reacts in the presence of inert organic solvents, Le A 21 533 or B) Ylidene-ß-ketoester of the general formula (II) ^ ₇ R-CH = C ₉ , (II) ^ CQR in which 1 2 '
R, R and R have the meaning given above, with amines of the general formula (IV) and ß-ketocarboxylic acid esters of the general formula (V) R ⁵ -NH ₂ R ³ '-CO-CH ₂ -CO ₂ R ⁴ (IV) (V) in which 5 3 '4
R, R and R have the meaning given above, optionally in the presence of inert organic solvents implements, or
■ '' C) Ylidene-ß-ketoester of the general formula (VI) Le A 21 533 ^ CO ₂ R ⁴ R-CH = C -, (VI) ^ COR in which 3 '4
R, R and R have the meaning given above, with enaminocarboxylic acid esters of the general formula (VII) R ² -C = CH-CO ₀ R ¹ (VII) 5 'R NH in which 2 '5 1
R, R and R have the meaning given above, optionally reacts in the presence of inert organic solvents, or D) Ylidene-ß-ketoester of the general formula (VI) R-CH = C ^ COR 3 (V ₁ ) in which 31 4
R, R and R have the meaning given above, with amines of the general formula (IV) Le A 21 533 - rf - R ⁵ -NH ₂ (IV) in which R has the meaning given above, and ß-ketocarboxylic acid esters of the general formula (VIII) R ² -CO-CH ₂ -CO ₂ R ¹ (VIII) in which 2 '1 R and R have the meaning given above, optionally in the presence of inert organic solvents or E) Aldehydes of the general formula (IX) R-C <^ (IX) in which R has the meaning given above, with enaminocarboxylic acid esters of the general formula (III) R ³ '-C = CH-CO ₉ R ⁴ (III) 5 'R NH Le A 21 533 in which 3 '4 5
R, R and R have the meaning given above, and with ß-ketocarboxylic acid esters of the general formula (VIII) R ² -CO-CH ₂ -CO ₂ R ¹ (VIII) in which 1 2 '
R and R which have the meaning given above, optionally reacts in the presence of inert organic solvents, or
F)
Aldehydes of the general formula (IX) (IX) ' in which R has the meaning given above, with enaminocarboxylic acid esters of the general formula (VII) R ² '-C = CH-CO ₉ R ¹ (VII) 5 '
R NH Le A 21 533 in which 12 '5
R, R and R have the meaning given above and with ß-ketocarboxylic acid esters of the general formula (V) R ³ '-CO-CH ₂ -CO ₂ R ⁴ (V) in which 3 '4
R and R have the meaning given above, optionally reacts in the presence of inert organic solvents, ο or
G)
in the event that X in the formula (I) denotes NH, 2 Il 3 Il and NR or R represent an amino group in which one 1. Ylidene-ß-ketoester of the general formula (II) ^R - ^{CH = C} \ (id in which 1 2
R, R and R have the meaning given above, 2
but R not for an amino or hydroxymethyl group stands, Le A 21 533 with amidinoacetic acid esters of the general formula (X) 4 C = CH-CO ₉ R (X) in which 4th
R has the meaning given above, optionally reacted in the presence of inert organic solvents or
2. Ylidene-ß-ketoester of the general formula (VI-) ^ CO "R ⁴ R-CH = C., (VI) in which 3 R, R and R have the meaning given above, but R does not represent an amino or hydroxymethyl group stands, with aminoacetic acid esters of the general Formula (XI) HN _x C = CH-CO ₉ R ¹ (XI) H ₂ N ^ in which R has the meaning given above, Le A 21 533 -ν « optionally in the presence of inert organic Causes solvent to react, or H) in the event that X in the general formula (I) stands for N-R, where R is as defined above has, and ■ II 3 "' R or R stand for the hydroxymethyl group by using the corresponding methods according to the invention 2 3 bonds where R or R is acetoxymethyl. interpret the terms of an acidic or basic Subjected to hydrolysis, whereby the acetoxymethyl group is converted into a hydroxymethyl group, or
I) in the event that X in the general formula (I) 2 3 " represents an oxygen atom and R or R represents an amino group, by 1. Ylidene-ß-ketoester of the general formula (II) ^ CO .-, R ¹ R-CH = C \ . (II) ^ COR Le A 21 533 - 92 - in which 1 2 ■ "■" "" ' R, R and R have the meaning given above, but R not for the amino or hydroxymethyl group stands, with cyanoacetic acid esters of the general formula (XII) N = C-CH ₂ -CO ₂ R ⁴ (XII) in which 4th
R has the meaning given above, optionally in the presence of organic solutions implements funds, or
2. Ylidene-ß-ketoester of the general formula (VI) ^ ₇
R-CH = C - (VI) ^ COR in which 4 3
R, R and R have the meaning given above, but R is not for the amino or hydroxymethyl group stands, with cyanoacetic acid esters of the general formula (XIII) N = C-CH ₂ -CO ₂ R ¹ (XIII) Le A 21 533 in which R has the meaning given above, optionally reacts in the presence of organic solvents, 5-; and the obtained compounds of the general Formula (I) optionally converted into their addition salts. 7. Medicaments contain at least one compound of the general formula (I) according to Claim 1. 8 · Process for the manufacture of medicines, thereby characterized in that compounds of the general formula (I) according to Claim 1 are optionally used converted from customary auxiliaries and carriers into a suitable application form. 9. Medicines with long-lasting circulatory effects containing at least one compound of the general formula (I) according to claim T. 10. · Use of compounds of the general formula (I) according to claim 1 in the fight against diseases Le A 21 533